Development of Asymmetric Cooperative Gold Catalysis and Beyond

协同催化或涉及金属-配体合作的催化是一种非常通用的方法。 催化产生了无数高效的合成方法，并赋予了 生物活性化合物和/或药物化合物的化学合成。尽管在这方面取得了非凡的进展 研究课题中，仍有很多需要开发新的基于独特配体设计的合作系统来 能够开发用于化学合成的新的和/或改进的合成方法。 2014年，PI启动了一项关于开发双功能联芳基-2-基膦配体的计划，这些配体是 旨在实现合作的金(I)催化。这些配体具有可以相互作用的远程碱性基团 在催化过程中与底物或试剂发生键合作用，从而实现配体-金属的协同作用。 几项初步研究，包括ppm级别的金催化的羧酸与炔的加成反应，以及 烯烃不对称异构化制烯丙烯及催化生成的σ-烯丙基金的捕集 以醛为中间体，验证了配体的设计和催化的协同性质。 作为国际和平研究所未来工作的主要重点，本提案寻求应用这种合作的金(I)催化 发展具有特殊综合价值的不对称变换的战略。这些措施包括 手性丁烯内酯和2，5-二取代吡咯烷的构筑及不对称丙烯酰化反应 反应/丙叉基C-H官能化。这一策略的推广到更便宜的合作铜(I) 而Ag(I)催化在不对称烯酸质子化反应中提供了新的和独特的机会，这将打开 获得各种羰基产品的宝贵途径。向官能化N，N-双齿配体的转变将 使合作配体设计概念能够应用于更广泛的金属催化和 提供了前所未有的机会，以不对称的方式操纵羰基化合物。 这项提议，如果实施，将引入一系列新的和多功能的手性双功能配体 金属催化，激发了在协同催化方面的研究努力。此外，开发的方法 将提供对化学合成具有高价值的各种手性结构的有效途径，并且 尤其是药品研发。

Cooperative catalysis or catalysis involving metal-ligand cooperation is a highly versatile approach in catalysis that have resulted in a myriad of highly efficient synthetic methods and conferred exceptional value to chemical synthesis of bioactive and/or pharmaceutical compounds. Despite extraordinary advances on this research topic, there are still much need to develop new cooperative systems based on unique ligand designs to enable the development of new and/or much improved synthetic methods for chemical synthesis. In 2014, the PI initiated a program on the development of bifunctional biaryl-2-ylphosphine ligands that are designed to enable cooperative gold(I) catalysis. These ligands feature remote basic groups that can engage bonding interactions with substrates or reagents during catalysis and thereby achieve ligand-metal cooperation. Several preliminary studies, including a ppm-level gold-catalyzed addition of carboxylic acid to alkyne, an asymmetric isomerization of alkyne into allene, and trapping of catalytically generated σ-allenylgold intermediate with aldehyde, have validated the ligand design and the cooperative nature of the catalysis. As the major focus of the PI’s future effort, this proposal seeks to apply this cooperative gold(I) catalysis strategy to the development of asymmetric transformations of exceptional synthetic values. These include expedient construction of chiral butenolids and 2,5-disubstituted pyrrolines and asymmetric propargylation reactions/propargylic C-H functionalizations. The extension of this strategy to much cheaper cooperative Cu(I) and Ag(I) catalysis offers new and distinct opportunities in asymmetric enolate protonation, which would open valuable access to various carbonyl products. The transition to functionalized N,N-bidentate ligands would enable the application of the cooperative ligand design concept to a much broader range of metal catalysis and offer unprecedented opportunities to manipulate carbonyl compounds in asymmetric manners. This proposal, if implemented, would introduce a range of new and versatile chiral bifunctional ligands to metal catalysis and inspire increasing research effort in cooperative catalysis. Moreover, the methods developed would provide efficient access to a variety of chiral structures of high value to chemical synthesis in general and pharmaceutical R&D in particular.